indianjophthalmol63293-1508341_041123

Uveal melanoma: Estimating prognosis

Swathi Kaliki, Carol L Shields1, Jerry A Shields1

Uveal melanoma is the most common primary malignant tumor of the eye in adults, predominantly found in Caucasians. Local tumor control of uveal melanoma is excellent, yet this malignancy is associated with relatively high mortality secondary to metastasis. Various clinical, histopathological, cytogenetic features and gene expression features help in estimating the prognosis of uveal melanoma. The clinical features associated with poor prognosis in patients with uveal melanoma include older age at presentation, male gender, larger tumor basal diameter and thickness, ciliary body location, diffuse tumor configuration, association with ocular/oculodermal melanocytosis, extraocular tumor extension, and advanced tumor staging by American Joint Committee on Cancer classification. Histopathological features suggestive of poor prognosis include epithelioid cell type, high mitotic activity, higher values of mean diameter of ten largest nucleoli, higher microvascular density, extravascular matrix patterns, tumorinfiltrating lymphocytes, tumorinfiltrating macrophages, higher expression of insulinlike growth factor1 receptor, and higher expression of human leukocyte antigen Class I and II. Monosomy 3, 1p loss, 6q loss, and 8q and those classified as Class II by gene expression are predictive of poor prognosis of uveal melanoma. In this review, we discuss the prognostic factors of uveal melanoma. A database search was performed on PubMed, using the terms uvea, iris, ciliary body, choroid, melanoma, uveal melanoma and prognosis, metastasis, genetic testing, gene expression profiling. Relevant English language articles were extracted, reviewed, and referenced appropriately.

Key words: Ciliary body, choroid, eye, iris, melanoma, metastasis, prognosis, tumor, uvea

Institute for Eye Cancer, L V Prasad Eye Institute, Banjara Hills, Support provided by Operation Eyesight Institute for Eye Cancer (SK) and Hyderabad Eye Research Foundation (SK), Hyderabad, India, 1Ocular Oncology Service, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, PA, USA

Correspondence to: Dr. Swathi Kaliki, Institute for Eye Cancer, L V Prasad Eye Institute, Hyderabad 500 034, Telangana, India. Email: [email protected]

Manuscript received: 05.03.14; Revision accepted: 20.09.14

Uveal melanoma represents 7981% of ocular melanomas and 35% of all melanomas.[13] In the United States, the incidence of uveal melanoma is 5/million population.[1] In Europe, the incidence of uveal melanoma follows a northtosouth decreasing gradient ranging from 2 to 8/million population.[2] Over the years, with advances in the treatment strategies, there is an improvement in the rate of local tumor control and globe salvage, but survival rate remains relatively unchanged.[1,4,5]

Uveal melanoma has a high tendency to metastasize resulting in high mortality.[1,510] The common sites of metastasis include liver (89%), lung (29%), and bone (17%).[8] Approximately, 50% of patients with uveal melanoma succumb to metastasis within 10 years of diagnosis, irrespective of the type of treatment.[1,510] Median survival after metastasis is 6 to 12 months, though longterm survival has been reported.[8,11] Though, the overall survival rate of patients with metastatic uveal melanoma is poor, median survival of patients receiving treatment for metastasis is better than those receiving no treatment.[8,1216]

Various clinical, histopathological, and cytogenetic features of uveal melanoma can identify those patients who are at high risk of developing metastasis and probably benefit from

appropriate prophylactic/therapeutic adjuvant and adjunctive treatments [Table 1]. In this review, we describe the features predictive of poor prognosis in patients with uveal melanoma. A database search was performed on PubMed, using the terms uvea, iris, ciliary body, choroid, melanoma, uveal melanoma and prognosis, metastasis, genetic testing, gene expression profiling (GEP). Relevant English language articles were extracted, reviewed, and referenced appropriately.

Clinical FeaturesThe clinical features predicting prognosis in patients with uveal melanoma include age at presentation, gender, tumor size, tumor location, tumor configuration, presence or absence of ocular/oculodermal melanocytosis (OM), extraocular tumor extension (EOE), and American Joint Committee on Cancer (AJCC) classification.[1765]

Age at presentationA few studies have concluded that the age of presentation has no influence on the prognosis of uveal melanoma.[1719] In contrast, other studies have indicated that the life prognosis is more favorable in children with uveal melanoma compared with adults.[2126] The favorable prognosis of uveal melanoma in children is attributed to a bias secondary to confounding factors such as higher percentage of iris melanoma, smaller tumor size at diagnosis, lower incidence of EOE, and shorter followup duration in children compared to adults.[2022] In an attempt to overcome these confounding factors, Kaliki et al. matched clinical predictive factors for metastasis such as gender, tumor location, tumor basal diameter, tumor thickness, extraocular extension, and followup duration in 122 patients in each age category (young [20 years], midadults [2160 years], older adults [>60 years]) and found that younger patient age

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at the time of diagnosis of uveal melanoma is associated with lower rate of metastasis compared with midadults and older adults.[27] Evaluation by decade of presentation in 8,033 patients with uveal melanoma by Shields et al. showed similar gradual increase in risk for metastasis with increasing age.[26] At 10 years, metastasis was 10% in patients aged 1120 years, 21% for 4150 years, and 30% for 7180 years.[26]

GenderThe Collaborative Ocular Melanoma Study (COMS) study group found no difference in uveal melanomarelated metastasis and death between men and women.[26] Other study groups made similar observations.[9,28] However, in a study of 723 uveal melanoma patients, Zloto et al. found significant gender differences in prognosis.[29] Male patients had worse prognosis with higher melanomarelated metastasis and death than female patients. Melanomarelated mortality in the first 10 years was twofold higher in males compared with females.[29] By multivariable regression analysis, Rietschel et al. found that male gender was associated with significantly higher risk of melanomarelated mortality than female gender.[30] The lower metastatic rate in females could be related to hormonal factors.[29,31] Zloto et al. suggested that estrogen may indirectly influence the tissue through the regulation of other factors that directly affect the melanoma or could be related to inhibitory action of estrogen on the growth of micrometastases within the liver.[29]

Tumor sizeTumor size (largest basal diameter and thickness) is one of the most important clinical prognostic feature of uveal melanoma.[6,7,9,30,3237] In a metaanalysis of 8 articles by DienerWest et al., the combined weighted estimates of 5year mortality rates associated with uveal melanoma were 16% for small tumors (2 mm tumor thickness and >16 mm basal diameter) by COMS group, melanomarelated mortality at 5 and 10 years was 28% and 40%, respectively, for patients in the enucleation treatment arm and 26% and 45% in the external beam radiotherapy preceding enucleation treatment arm.[32,33]

In a longterm study of 289 patients with uveal melanoma, Kujala et al. found significant association between largest basal diameter of the tumor and melanomarelated mortality.[9] By competing risks regression analysis, the Hazard ratio was 1.08 for each millimeter increase in tumor diameter. The cumulative incidence estimates of melanomarelated mortality increased with increasing tumor basal diameter at 18% for small tumors (

February 2015 Kaliki, et al.: Prognosis of uveal melanoma 95

thinner tumors for metastatic disease and melanomarelated death.[43] According to Li et al., there is a significant relation between degree of ciliary body involvement (% of tumor base within the ciliary body) and melanomarelated metastasis.[44] According to this study, a melanoma of presumed ciliary body origin (>50% of the tumor base within the ciliary body) had 1.62.3 times higher chance of metastasis than a choroidal (


Callender classification showed an improved correlation between the cell type and the mortality.[66]

In a study of 2652 enucleated eyes with uveal melanoma by Paul et al., the 15year mortality for spindle A tumor was 19%, spindle B was 26%, mixed spindle B and epithelioid was 59%, and epithelioid tumor was 72%.[67] The 15year mortality of patients with melanomas of mixed cell type is three times that of patients with tumors of pure spindle cell type.[37] Various studies have established that the spindle cell uveal melanoma has the best prognosis, mixed cell melanoma an intermediate, and epithelioid cell melanoma has the worst prognosis.[37,40,61,6770] The prognosis worsens with increasing number of epithelioid cells per high power field (HPF).[69] In a study of 232 enucleated eyes from patients with uveal melanoma, the 10year survival was 82% in patients with 5 epithelioid cells/HPF.[69]

Mitotic activityTumors with high cellular proliferation have a poor prognosis. Cellular proliferation in uveal melanoma can be determined by counting number of mitoses per 40 HPFs. Tumors with a low mitotic activity have a relatively good prognosis compared to those showing high mitotic activity.[71] In a study of 217 small malignant melanomas by McLean et al., increase in the number of mitoses/40 HPFs was significantly associated with increasing mortality rate. Sixyear mortality was 16% for 0 mitosis/40 HPSs, 23% for 1mitosis/40 HPFs, 40% for 24, 47% for 58, and 56% for 948 mitoses/40 HPFs.[71]

In recent years immunohistochemical markers, PC10 for proliferating cell nuclear antigen and MIB1 for Ki67 are used to examine cellular proliferation in conventionally processed histological preparations.[7277] These markers seem to be reliable and easy tools for evaluating cellular activity. A high fraction of PC10 and Ki67 in uveal melanoma cells is associated with decreased melanomaspecific survival.[77,78]

Mean diameter of ten largest nucleoliA large mean diameter of ten largest nucleoli (MLN) is associated with poor prognosis.[37,7985] MLN can be measured on silver or hematoxylineosin stained sections. Larger MLN is found in tumors with epithelioid cells and in those with increasing MVD, which could influence poor prognosis.[79,81,85] However, studies have shown that larger MLN is an independent predictor of melanomarelated mortality.[79,83,84] There is a 0.581.27 times increase in melanomarelated mortality for each 1um increase in MLN.[7984]

In a study of 167 specimens for MLN, the median MLN was 4.05um (range, 2.606.18sum).[79] The 10year KaplanMeier estimate for melanomaspecific survival was 74% for small, 60% for medium, and 42% for large MLN.[79] MLN remained an independent predictor of prognosis, when adjusted in turn for the effect of ciliary body involvement, largest tumor basal diameter, presence of epithelioid cells, and microvascular loops and networks. When adjusted for MVD, it was of borderline significance. However, combined MLN with cell type and MVD best predicted melanomaspecific survival.[79]

Microvascular densityMVD is a quantitative measurement of tumor vascularity. Microvessels are more distinct and easier to count from

sections immunolabeled for CD34 epitope or FVIIIRag.[86,87] Noninvasive methods of detection of MVD by ultrasound parameter imaging and confocal microscopy are also described.[8890] High MVD is associated with a shortened survival of patients with uveal melanoma.[79,86,87,91] There is a significant association between high MVD and presence of microvascular loops and networks, epithelioid cells, and largest basal tumor diameter, thus influencing poor prognosis.[86,87] High MVD alone can also serve as an independent risk factor for melanomarelated metastasis and death.[79,87]

In a study of 162 consecutive enucleation specimens by Mkitie et al., the median MVD was 40 vessels/0.313 mm2 (range, 5121).[87] The 10year melanomaspecific mortality increased from quartile to quartile with increasing MVD, at 9%, 29%, 59%, and 64% according to quartiles.[87] Similar results were shown by Foss et al., with estimated 9year cumulative probabilities of survival for the four quartiles at 85%, 55%, 44%, and 27%, respectively.[86]

Extravascular matrix patternsThe concept of microvascular patterns was introduced by Folberg et al., who suggested that microvessel architecture has a strong association with prognosis of uveal melanoma.[92] In addition to normal vessels incorporated into the tumor stroma and focal avascular zones, the tumors contain straight vessels, parallel straight vessels, parallel vessels that crosslink, vascular arcs (incomplete loops), arcs with branching, closed vascular loops that encircle small clusters of tumor cells, and microvascular networks composed of backtoback loops.[92] The patterns are assessed with light microscopy on periodicacidschiff stained tissues.

The presence of microvascular loops and networks surrounding nests of tumor cells can independently predict melanomarelated tumor death.[9294] In a matched case control study by Folberg et al., it was shown that the presence of at least one closed vascular loop in a uveal melanoma is the most significant vascular pattern associated with death from metastatic melanoma.[92] The detection of at least one closed loop within a tumor is associated with the presence of epithelioid cells and at least one mitotic figure.[92] In a study by AlJamal et al., the KaplanMeier estimate for 10year melanomaspecific survival was estimated at 80% if no loops, 48% if loops were present without networks, and 40% if loops forming networks were present.[79]

Tumor infiltrating lymphocytesIncreased infiltration of uveal melanoma by lymphocytes suggests poor prognosis.[9598] An association between monosomy 3 and influx of tumorinfiltrating lymphocytes has been established.[97] Uveal melanoma cells which have lost one copy of chromosome 3 may produce inflammatory mediators, which recruit and activate CD8+, CD4+, and Foxp3+ T cells, as well as CD68+, and CD68+ and CD163+ macrophages. Activation of these infiltrating cells will result in production of more inflammatory mediators generating a tumorpromoting inflammatory microenvironment, resulting in poor prognosis.[98]

In a study of 1193 cases by de la Cruz et al., 134 (12%) tumors contained 100 or more lymphocytes per 20 HPF and were classified as high lymphocytic group.[95] An equivalent number of cases with fewer lymphocytes comprised the low lymphocytic group. The survival rate at 15 years was 37% for



patients in the high lymphocytic group and 70% for patients in the low lymphocytic group. Despite control of other risk factors, there was a significant association between increased number of lymphocytes per 20 HPF and survival.[95]

Tumor infiltrating macrophagesHigh numbers of tumorinfiltrating macrophages in uveal melanoma are associated with an unfavorable prognosis.[99104] These tumors are associated with the presence of epithelioid cells, increased MVD, and monosomy 3.[99103] Macrophages of the M2 phenotype promotes phagocytic activity, tissue remodeling, tumor progression, and angiogenesis.[104]

In a study of 43 uveal melanomas by immunohistochemistry, the infi ltrating macrophages were predominantly CD68+ CD163+ (M2 phenotype).[104] KaplanMeier survival analysis revealed that a low CD68+ or CD68+ CD163+ macrophages were associated with a significantly better survival. However, the significance of tumorinfiltrating macrophages as a predictor of melanomarelated mortality could not be established on multivariable analysis.[104]

Insulinlike growth factor1 receptorHigh expression levels of IGF1R in primary tumors correlates significantly with lower survival rates.[105] The significant association between high IGF1R expression and death due to metastatic disease may be related to the fact that IGF1 is mainly produced in the liver, which is the preferential site for uveal melanoma metastases.[105] Based on this finding, IGF1R blockage is a possible new treatment modality for metastases that may also play a role as adjuvant therapy in preventing the development of metastatic disease;[106] and serum IGF1 level may be used as a predictive biomarker for metastatic uveal melanoma when measured repeatedly.[107]

In a study of 36 cases of uveal melanoma with more than 15 years followup, KaplanMeier analysis showed a significant association between a high IGF1R (expression in >50% melanoma cells) and melanomarelated mortality.[105] Over a period of 15 years followup, 56% of patients with high IGF1R, and 42% with low IGF1R (expression in 15 to 50% cells), and 0% with very low IGF1R (expression in


abnormality, 31% with only 8q gain, 40% with only monosomy 3, and 66% with combined 8q gain and monosomy 3.[118] 8q gain was associated with clinical and histopathologic risk factors, including larger tumor diameter, ciliary body tumor location, epithelioid cell type, high mitotic rate, and vascular loops.[118]

Chromosome 1Loss of part or all of chromosome 1p is associated with poor prognosis either when it presents alone or coexists with monosomy 3.[120,121] Chromosome 1p loss occurs more frequently in tumors with monosomy 3 (40%) than those with disomy 3 (10%).[121]

Concomitant loss of chromosomes 1p and 3 has a stronger correlation with melanomarelated metastasis than either one of them separately. In a study 0f 120 patients with uveal melanoma by Kilic et al., it was noted that the effect of monosomy 3 on survival was largely modified by changes in 1p36.[120] After correcting for confounding variables, it was found that patients harboring tumors with concurrent loss of chromosomes 1p36 and 3 have 7.8 times higher chance of developing metastases than do those without these losses or with loss of either chromosomes 1p36 or 3.[120]

Chromosome 6Chromosome 6 gain has an inverse relationship with melanomarelated metastasis, and is a strong indicator of good prognosis of uveal melanoma.[114,119] Chromosome 6p gain is usually mutually exclusive with monosomy 3.[114,131] These tumors with chromosome 6p gain have been proposed to represent a separate group of uveal melanomas with an alternative genetic pathway in carcinogenesis compared with those with monosomy 3.[131,132] The coexistence of 6p gain and monosomy 3 occurs in only 4% cases of uveal melanoma.[132]

Chromosome 6q loss is associated with poor prognosis. In a study of 35 tumors by Aalto et al., 6q loss was noted in 40% metastasizing tumors when compared to 7% nonmetastasizing tumors.[133]

Transcriptomic FeaturesBased on analysis of mRNA by GEP of all chromosomes, 2 tumor classes of uveal melanoma were described by Tschentscher et al.[134] All tumors in Class I had disomy 3, and all tumors in Class II had monosomy 3.[134] Subsequently, a relationship between GEP and melanomarelated survival in patients with uveal melanoma was studied by Onken et al.[135] Based on the comparison of molecular classification to cytogenetic changes in 10 tumor samples, Class I tumors were considered as lowrisk tumors and Class II tumors as highrisk tumors.[135] Chromosome 6p gain occurred in 80% Class I tumors, and monosomy 3 was noted in 80% Class II tumors and no Class I tumors.[135] Survival analysis of 50 patients revealed 95% survival probability in Class I versus 31% in class 2 at 7.7 years followup.[135] Subsequent studies noted similar findings. Class I lesions were unlikely to undergo metastasis, whereas Class II lesions predicted a greater rate of metastasis and melanomarelated mortality.[135140] Patients with Class II tumors tend to be older, and are associated with thicker tumors, epithelioid cytology, higher proliferative rate (higher Ki67 positivity), and mutations in BAP1 tumor suppressor gene.[127,138,139]

A recent study of 459 patients with uveal melanoma by a multicenter trial from 12 oncology centers, revealed a strong

association between GEP and prognosis of uveal melanoma.[140] At a median of 17 months followup, metastasis was detected in 1% Class I cases and 26% Class II cases.[140] GEP class had a strong independent association with metastasis and chromosome 3 status did not provide additional prognostic information that was independent of GEP.[140]

ConclusionThe longterm prognosis of uveal melanoma is poor with

death occurring in more than 50% cases. The prognosis of uveal melanoma can be estimated by clinical, histopathological, cytogenetic, and transcriptomic markers. Improved prognostication for uveal melanoma allows identification of patients at high risk for metastasis, thereby facilitating targeted screening, and probable adjunctive/adjuvant systemic treatment. Currently, the most effective measure to minimize poor prognosis is early detection of melanoma at a time when the tumor is small and at least risk for metastatic disease.

References1. Singh AD, Turell ME, Topham AK. Uveal melanoma: Trends in

incidence, treatment, and survival. Ophthalmology 2011;118:18815.

2. Virgili G, Gatta G, Ciccolallo L, Capocaccia R, Biggeri A, Crocetti E, et al. Incidence of uveal melanoma in Europe. Ophthalmology 2007;114:230915.

3. Chang AE, Karnell LH, Menck HR. The National Cancer Data Base report on cutaneous and noncutaneous melanoma: A summary of 84,836 cases from the past decade. The American College of Surgeons Commission on Cancer and the American Cancer Society. Cancer 1998;83:166478.

4. Jampol LM, Moy CS, Murray TG, Reynolds SM, Albert DM, Schachat AP, et al. The COMS randomized trial of iodine 125 brachytherapy for choroidal melanoma: IV. Local treatment failure and enucleation in the first 5 years after brachytherapy. COMS report no 19. Ophthalmology 2002;109:2197206.

5. Virgili G, Gatta G, Ciccolallo L, Capocaccia R, Biggeri A, Crocetti E, et al. Survival in patients with uveal melanoma in Europe. Arch Ophthalmol 2008;126:14138.

6. Collaborative Ocular Melanoma Study Group. The COMS randomized trial of iodine 125 brachytherapy for choroidal melanoma: V. Twelveyear mortality rates and prognostic factors: COMS report No 28. Arch Ophthalmol 2006;124:168493.

7. DienerWest M, Hawkins BS, Markowitz JA, Schachat AP. A review of mortality from choroidal melanoma. II. A metaanalysis of 5year mortality rates following enucleation, 1966 through 1988. Arch Ophthalmol 1992;110:24550.

8. DienerWest M, Reynolds SM, Agugliaro DJ, Caldwell R, Cumming K, Earle JD, et al. Development of metastatic disease after enrollment in the COMS trials for treatment of choroidal melanoma: Collaborative Ocular Melanoma Study Group Report No 26. Arch Ophthalmol 2005;123:163943.

9. Kujala E, Mkitie T, Kivel T. Very longterm prognosis of patients with malignant uveal melanoma. Invest Ophthalmol Vis Sci 2003;44:46519.

10. Gamel JW, McLean IW, McCurdy JB. Biologic distinctions between cure and time to death in 2892 patients with intraocular melanoma. Cancer 1993;71:2299305.

11. Duh EJ, Schachat AP, Albert DM, Patel SM. Longterm survival in a patient with uveal melanoma and liver metastasis. Arch Ophthalmol 2004;122:2857.

12. Gragoudas ES, Egan KM, Seddon JM, Glynn RJ, Walsh SM, Finn SM, et al. Survival of patients with metastases from uveal melanoma. Ophthalmology 1991;98:3839.



13. Eschelman DJ, Gonsalves CF, Sato T. Transhepatic therapies for metastatic uveal melanoma. Semin Intervent Radiol 2013;30:3948.

14. Buder K, Gesierich A, Gelbrich G, Goebeler M. Systemic treatment of metastatic uveal melanoma: Review of literature and future perspectives. Cancer Med 2013;2:67486.

15. Gomez D, Wetherill C, Cheong J, Jones L, Marshall E, Damato B, et al. The Liverpool uveal melanoma liver metastases pathway: Outcome following liver resection. J Surg Oncol 2014;109:5427.

16. Yamamoto A, Chervoneva I, Sullivan KL, Eschelman DJ, G o n s a l ve s C F , M a s t r a n g e l o M J , e t a l . H i g h d o s e immunoembolization: Survival benefit in patients with hepatic metastases from uveal melanoma. Radiology 2009;252:2908.

17. Apt L. Uveal melanomas in children and adolescents. Int Ophthalmol Clin 1962;2:40310.

18. Paul EV, Parnell BL, Fraker M. Prognosis of malignant melanomas of the choroid and ciliary body. Int Ophthalmol Clin 1962;2:387402.

19. Barr CC, McLean IW, Zimmerman LE. Uveal melanoma in children and adolescents. Arch Ophthalmol 1981;99:21336.

20. Shields CL, Shields JA, Milite J, De Potter P, Sabbagh R, Menduke H. Uveal melanoma in teenagers and children. A report of 40 cases. Ophthalmology 1991;98:16626.

21. Pogrzebielski A, OrowskaHeitzman J, RomanowskaDixon B. Uveal melanoma in young patients. Graefes Arch Clin Exp Ophthalmol 2006;244:16469.

22. Singh AD, Shields CL, Shields JA, Sato T. Uveal melanoma in young patients. Arch Ophthalmol 2000;118:91823.

23. Leonard BC, Shields JA, McDonald PR. Malignant melanomas of the uveal tract in children and young adults. Can J Ophthalmol 1975;10:4419.

24. Jensen OA. Malignant melanomas of the human uvea: 25year followup of cases in Denmark, 19431952. Acta Ophthalmol (Copenh) 1982;60:16182.

25. Verdaguer J Jr. Prepuberal and puberal melanomas in ophthalmology. Am J Ophthalmol 1965;60:100211.

26. Shields CL, Kaliki S, Furuta M, Mashayekhi A, Shields JA. Clinical spectrum and prognosis of uveal melanoma based on age at presentation in 8,033 cases. Retina 2012;32:136372.

27. Kaliki S, Shields CL, Mashayekhi A, Ganesh A, Furuta M, Shields JA. Influence of age on prognosis of young patients with uveal melanoma: A matched retrospective cohort study. Eur J Ophthalmol 2013;23:20816.

28. Bergman L, Seregard S, Nilsson B, Lundell G, Ringborg U, RagnarssonOlding B. Uveal melanoma survival in Sweden from 1960 to 1998. Invest Ophthalmol Vis Sci 2003;44:32827.

29. Zloto O, Peer J, Frenkel S. Gender differences in clinical presentation and prognosis of uveal melanoma. Invest Ophthalmol Vis Sci 2013;54:6526.

30. Rietschel P, Panageas KS, Hanlon C, Patel A, Abramson DH, Chapman PB. Variates of survival in metastatic uveal melanoma. J Clin Oncol 2005;23:807680.

31. Holly EA, Aston DA, Ahn DK, Kristiansen JJ, Char DH. Uveal melanoma, hormonal and reproductive factors in women. Cancer Res 1991;51:13702.

32. The Collaborative Ocular Melanoma Study (COMS) randomized trial of preenucleation radiation of large choroidal melanoma II: Initial mortality findings. COMS report no 10. Am J Ophthalmol 1998;125:77996.

33. Hawkins BS, Collaborative Ocular Melanoma Study Group. The Collaborative Ocular Melanoma Study (COMS) randomized trial of preenucleation radiation of large choroidal melanoma: IV. Tenyear mortality findings and prognostic factors. COMS report number 24. Am J Ophthalmol 2004;138:93651.

34. S h i e l d s C L , F u r u t a M , T h a n g a p p a n A , N a g o r i S ,

Mashayekhi A, Lally DR, et al. Metastasis of uveal melanoma millimeterbymillimeter in 8033 consecutive eyes. Arch Ophthalmol 2009;127:98998.

35. Damato B, Coupland SE. A reappraisal of the significance of largest basal diameter of posterior uveal melanoma. Eye (Lond) 2009;23:215260.

36. Augsburger JJ, Gamel JW. Clinical prognostic factors in patients with posterior uveal malignant melanoma. Cancer 1990;66:1596600.

37. McLean IW, Foster WD, Zimmerman LE. Uveal melanoma: Location, size, cell type, and enucleation as risk factors in metastasis. Hum Pathol 1982;13:12332.

38. Shields CL, Kaliki S, Shah SU, Luo W, Furuta M, Shields JA. Iris melanoma: Features and prognosis in 317 children and adults. J AAPOS 2012;16:106.

39. Prescher G, Bornfeld N, Hirche H, Horsthemke B, Jckel KH, Becher R. Prognostic implications of monosomy 3 in uveal melanoma. Lancet 1996;347:12225.

40. Seddon JM, Albert DM, Lavin PT, Robinson N. A prognostic factor study of diseasefree interval and survival following enucleation for uveal melanoma. Arch Ophthalmol 1983;101:18949.

41. Damato B, Duke C, Coupland SE, Hiscott P, Smith PA, Campbell I, et al. Cytogenetics of uveal melanoma: A 7year clinical experience. Ophthalmology 2007;114:192531.

42. Kivel T. Iris melanomas in children. Arch Ophthalmol 2001;119:9256.

43. Gndz K, Shields CL, Shields JA, Cater J, Freire JE, Brady LW. Plaque radiotherapy of uveal melanoma with predominant ciliary body involvement. Arch Ophthalmol 1999;117:1707.

44. Li W, Gragoudas ES, Egan KM. Metastatic melanoma death rates by anatomic site after proton beam irradiation for uveal melanoma. Arch Ophthalmol 2000;118:106670.

45. Rummelt V, Folberg R, Woolson RF, Hwang T, Peer J. Relation between the microcirculation architecture and the aggressive behavior of ciliary body melanomas. Ophthalmology 1995;102:84451.

46. Font RL, Spaulding AG, Zimmerman LE. Diffuse malignant melanoma of the uveal tract: A clinicopathologic report of 54 cases. Trans Am Acad Ophthalmol Otolaryngol 1968;72:87795.

47. Rones B, Zimmerman LE. The production of heterochromia and glaucoma by diffuse malignant melanoma of the iris. Trans Am Acad Ophthalmol Otolaryngol 1957;61:44763.

48. Demirci H, Shields CL, Shields JA, Eagle RC Jr, Honavar SG. Diffuse iris melanoma: A report of 25 cases. Ophthalmology 2002;109:155360.

49. Demirci H, Shields CL, Shields JA, Honavar SG, Eagle RC Jr. Ring melanoma of the ciliary body: Report on twentythree patients. Retina 2002;22:698706.

50. Shields CL, Kaliki S, Furuta M, Shields JA. Diffuse versus nondiffuse small (=3 MM thickness) choroidal melanoma: Comparative analysis in 1,751 cases. The 2012 F. Phinizy Calhoun lecture. Retina 2013;33:176376.

51. Parsons JH. Diffuse sarcomata of the uveal tract. Arch Ophthalmol 1904;33:10112.

52. Rones B, Zimmerman LE. The prognosis of primary tumors of the iris treated by iridectomy. AMA Arch Ophthalmol 1958;60:193205.

53. Shields CL, Shields JA, Materin M, Gershenbaum E, Singh AD, Smith A. Iris melanoma: Risk factors for metastasis in 169 consecutive patients. Ophthalmology 2001;108:1728.

54. Singh AD, De Potter P, Fijal BA, Shields CL, Shields JA, Elston RC. Lifetime prevalence of uveal melanoma in white patients with oculo (dermal) melanocytosis. Ophthalmology 1998;105:1958.



55. Shields CL, Kaliki S, Livesey M, Walker B, Garoon R, Bucci M, et al. Association of ocular and oculodermal melanocytosis with the rate of uveal melanoma metastasis: Analysis of 7872 consecutive eyes. JAMA Ophthalmol 2013;131:9931003.

56. Mashayekhi A, Kaliki S, Walker B, Park C, Sinha N, Kremer FZ, et al. Metastasis from uveal melanoma associated with congenital ocular melanocytosis: A matched study. Ophthalmology 2013;120:14658.

57. Affeldt JC, Minckler DS, Azen SP, Yeh L. Prognosis in uveal melanoma with extrascleral extension. Arch Ophthalmol 1980;98:19759.

58. Pach JM, Robertson DM, Taney BS, Martin JA, Campbell RJ, OBrien PC. Prognostic factors in choroidal and ciliary body melanomas with extrascleral extension. Am J Ophthalmol 1986;101:32531.

59. Gndz K, Shields CL, Shields JA, Cater J, Brady L. Plaque radiotherapy for management of ciliary body and choroidal melanoma with extraocular extension. Am J Ophthalmol 2000;130:97102.

60. Histopathologic characteristics of uveal melanomas in eyes enucleated from the Collaborative Ocular Melanoma Study. COMS report no 6. Am J Ophthalmol 1998;125:74566.

61. Coupland SE, Campbell I, Damato B. Routes of extraocular extension of uveal melanoma: Risk factors and influence on survival probability. Ophthalmology 2008;115:177885.

62. Edge SB, Fritz AG, Byrd DR, Greene FL, Trotti III A, Compton CC, editors. AJCC Cancer Staging Manual. 7th ed. New York: Springer; 2010. p. 54759.

63. Shields CL, Kaliki S, Peshtani A, Alarcon C, Fulco E, Komati R, et al. American Joint Committee on Cancer (AJCC) classification of iris melanoma is predictive of patient prognosis. Analysis of 452 patients. Submitted for publication.

64. Shields CL, Kaliki S, Furuta M, Fulco E, Alarcon C, Shields JA. American Joint Committee on Cancer classification of posterior uveal melanoma (tumor size category) predicts prognosis in 7731 patients. Ophthalmology 2013;120:206671.

65. Callender GR. Malignant melanotic tumors of the eye. A study of histologic types in 111 cases. Trans Am Acad Ophthalmol Otolaryngol 1931;36:13140.

66. McLean IW, Foster WD, Zimmerman LE, Gamel JW. Modifications of Callenders classification of uveal melanoma at the Armed Forces Institute of Pathology. Am J Ophthalmol 1983;96:5029.

67. Paul EV, Parnell BI, Fraker M. Prognosis of malignant melanomas of the choroid and ciliary body. Int Ophthalmol Clin 1962;2:387402.

68. Seregard S, Kock E. Prognostic indicators following enucleation for posterior uveal melanoma. A multivariate analysis of longterm survival with minimized loss to followup. Acta Ophthalmol Scand 1995;73:3404.

69. Seddon JM, Polivogianis L, Hsieh CC, Albert DM, Gamel JW, Gragoudas ES. Death from uveal melanoma. Number of epithelioid cells and inverse SD of nucleolar area as prognostic factors. Arch Ophthalmol 1987;105:8016.

70. Gamel JW, McLean IW, Foster WD, Zimmerman LE. Uveal melanomas: Correlation of cytologic features with prognosis. Cancer 1978;41:1897901.

71. McLean MJ, Foster WD, Zimmerman LE. Prognostic factors in small malignant melanomas of choroid and ciliary body. Arch Ophthalmol 1977;95:4858.

72. Peer J, Gnessin H, Shargal Y, Livni N. PC10 immunostaining of proliferating cell nuclear antigen in posterior uveal melanoma. Enucleation versus enucleation postirradiation groups. Ophthalmology 1994;101:5662.

73. Seregard S, Lundell G, Lax I, af Trampe E, Kock E. Tumour cell proliferation after failed ruthenium plaque radiotherapy for posterior uveal melanoma. Acta Ophthalmol Scand 1997;75:14854.

74. Schilling H, Sehu KW, Lee WR. A histologic study (including DNA quantification and Ki67 labeling index) in uveal melanomas after brachytherapy with ruthenium plaques. Invest Ophthalmol Vis Sci 1997;38:208192.

75. Chiquet C, Grange JD, Ayzac L, Chauvel P, Patricot LM, DevouassouxShisheboran M. Effects of proton beam irradiation on uveal melanomas: A comparative study of Ki67 expression in irradiated versus nonirradiated melanomas. Br J Ophthalmol 2000;84:98102.

76. Peer J, Stefani FH, Seregard S, Kivela T, Lommatzsch P, Prause JU, et al. Cell proliferation activity in posterior uveal melanoma after Ru106 brachytherapy: An EORTC ocular oncology group study. Br J Ophthalmol 2001;85:120812.

77. Karlsson M, Boeryd B, Carstensen J, Frnlund B, Gustafsson B, Kgedal B, et al. Correlations of Ki67 and PCNA to DNA ploidy, Sphase fraction and survival in uveal melanoma. Eur J Cancer 1996;32A: 35762.

78. Mooy CM, Luyten GP, de Jong PT, Luider TM, Stijnen T, van de Ham F, et al. Immunohistochemical and prognostic analysis of apoptosis and proliferation in uveal melanoma. Am J Pathol 1995;147:1097104.

79. AlJamal RT, Mkitie T, Kivel T. Nucleolar diameter and microvascular factors as independent predictors of mortality from malignant melanoma of the choroid and ciliary body. Invest Ophthalmol Vis Sci 2003;44:23819.

80. Huntington A, Haugan P, Gamel J, McLean I. A simple cytologic method for predicting the malignant potential of intraocular melanoma. Pathol Res Pract 1989;185:6314.

81. Moshari A, McLean IW. Uveal melanoma: Mean of the longest nucleoli measured on silverstained sections. Invest Ophthalmol Vis Sci 2001;42:11603.

82. McCurdy J, Gamel J, McLean I. A simple, efficient, and reproducible method for estimating the malignant potential of uveal melanoma from routine H and E slides. Pathol Res Pract 1991;187:10257.

83. Srensen FB, Gamel JW, McCurdy J. Stereologic estimation of nucleolar volume in ocular melanoma: A comparative study of size estimators with prognostic impact. Hum Pathol 1993;24:5138.

84. McLean IW, Sibug ME, Becker RL, McCurdy JB. Uveal melanoma: The importance of large nucleoli in predicting patient outcome an automated image analysis study. Cancer 1997;79:9828.

85. Peer J, Rummelt V, Mawn L, Hwang T, Woolson RF, Folberg R. Mean of the ten largest nucleoli, microcirculation architecture, and prognosis of ciliochoroidal melanomas. Ophthalmology 1994;101:122735.

86. Foss AJ, Alexander RA, Jefferies LW, Hungerford JL, Harris AL, Lightman S. Microvessel count predicts survival in uveal melanoma. Cancer Res 1996;56:29003.

87. Mkitie T, Summanen P, Tarkkanen A, Kivel T. Microvascular density in predicting survival of patients with choroidal and ciliary body melanoma. Invest Ophthalmol Vis Sci 1999;40:247180.

88. Silverman RH, Folberg R, Boldt HC, Lloyd HO, Rondeau MJ, Mehaffey MG, et al. Correlation of ultrasound parameter imaging with microcirculatory patterns in uveal melanomas. Ultrasound Med Biol 1997;23:57381.

89. Coleman DJ, Silverman RH, Rondeau MJ, Boldt HC, Lloyd HO, Lizzi FL, et al. Noninvasive in vivo detection of prognostic indicators for highrisk uveal melanoma: Ultrasound parameter imaging. Ophthalmology 2004;111:55864.

90. Mueller AJ, Bartsch DU, Folberg R, Mehaffey MG, Boldt HC, Meyer M, et al. Imaging the microvasculature of choroidal melanomas with confocal indocyanine green scanning laser ophthalmoscopy. Arch Ophthalmol 1998;116:319.

91. Chen X, Maniotis AJ, Majumdar D, Peer J, Folberg R. Uveal melanoma cell staining for CD34 and assessment of tumor vascularity. Invest Ophthalmol Vis Sci 2002;43:25339.



92. Folberg R, Peer J, Gruman LM, Woolson RF, Jeng G, Montague PR, et al. The morphologic characteristics of tumor blood vessels as a marker of tumor progression in primary human uveal melanoma: A matched casecontrol study. Hum Pathol 1992;23:1298305.

93. Mkitie T, Summanen P, Tarkkanen A, Kivel T. Microvascular loops and networks as prognostic indicators in choroidal and ciliary body melanomas. J Natl Cancer Inst 1999;91:35967.

94. Kivel T, Mkitie T, AlJamal RT, Toivonen P. Microvascular loops and networks in uveal melanoma. Can J Ophthalmol 2004;39:40921.

95. De la Cruz PO Jr, Specht CS, McLean IW. Lymphocytic infiltration in uveal malignant melanoma. Cancer 1990;65:1125.

96. Whelche l JC , Farah SE , McLean IW, Burnier MN. Immunohistochemistry of infiltrating lymphocytes in uveal malignant melanoma. Invest Ophthalmol Vis Sci 1993;34:26036.

97. Bronkhorst IH, Vu TH, Jordanova ES, Luyten GP, Burg SH, Jager MJ. Different subsets of tumorinfiltrating lymphocytes correlate with macrophage influx and monosomy 3 in uveal melanoma. Invest Ophthalmol Vis Sci 2012;53:53708.

98. Bronkhorst IH, Jager MJ. Uveal melanoma: The inflammatory microenvironment. J Innate Immun 2012;4:45462.

99. Mkitie T, Summanen P, Tarkkanen A, Kivel T. Tumorinfiltrating macrophages (CD68(+) cells) and prognosis in malignant uveal melanoma. Invest Ophthalmol Vis Sci 2001;42:141421.

100. Toivonen P, Mkitie T, Kujala E, Kivel T. Macrophages and microcirculation in regressed and partially regressed irradiated choroidal and ciliary body melanomas. Curr Eye Res 2003;27:23745.

101. Bronkhorst IH, Ly LV, Jordanova ES, Vrolijk J, Versluis M, Luyten GP, et al. Detection of M2macrophages in uveal melanoma and relation with survival. Invest Ophthalmol Vis Sci 2011;52:64350.

102. Maat W, Ly LV, Jordanova ES, de WolffRouendaal D, SchalijDelfos NE, Jager MJ. Monosomy of chromosome 3 and an inflammatory phenotype occur together in uveal melanoma. Invest Ophthalmol Vis Sci 2008;49:50510.

103. Vu TH, Bronkhorst IH, Versluis M, Marinkovic M, van Duinen SG, Vrolijk J, et al. Analysis of inflammatory cells in uveal melanoma after prior irradiation. Invest Ophthalmol Vis Sci 2013;54:3609.

104. Herwig MC, Grossniklaus HE. Role of macrophages in uveal melanoma. Expert Rev Ophthalmol 2011;6:40507.

105. AllEricsson C, Girnita L, Seregard S, Bartolazzi A, Jager MJ, Larsson O. Insulinlike growth factor1 receptor in uveal melanoma: A predictor for metastatic disease and a potential therapeutic target. Invest Ophthalmol Vis Sci 2002;43:18.

106. Girnita A, AllEricsson C, Economou MA, Astrm K, Axelson M, Seregard S, et al. The insulinlike growth factorI receptor inhibitor picropodophyllin causes tumor regression and attenuates mechanisms involved in invasion of uveal melanoma cells. Clin Cancer Res 2006;12:138391.

107. Frenkel S, Zloto O, Peer J, Barak V. Insulinlike growth factor1 as a predictive biomarker for metastatic uveal melanoma in humans. Invest Ophthalmol Vis Sci 2013;54:4903.

108. Cohen EP, Kim TS. Neoplastic cells that express low levels of MHC class I determinants escape host immunity. Semin Cancer Biol 1994;5:41928.

109. Jager MJ, Hurks HM, Levitskaya J, Kiessling R. HLA expression in uveal melanoma: There is no rule without some exception. Hum Immunol 2002;63:44451.

110. Blom DJ, Luyten GP, Mooy C, Kerkvliet S, Zwinderman AH, Jager MJ. Human leukocyte antigen class I expression. Marker of poor prognosis in uveal melanoma. Invest Ophthalmol Vis Sci 1997;38:186572.

111. Ericsson C, Seregard S, Bartolazzi A, Levitskaya E, Ferrone S, Kiessling R, et al. Association of HLA class I and class II antigen

expression and mortality in uveal melanoma. Invest Ophthalmol Vis Sci 2001;42:21536.

112. Krishnakumar S, Abhyankar D, Lakshmi SA, Pushparaj V, Shanmugam MP, Biswas J. HLA expression in choroidal melanomas: Correlation with clinicopathological features. Curr Eye Res 2004;28:40916.

113. Jager MJ, de WolffRouendaal D, Breebaart AC, Ruiter DJ. Expression of HLA antigens in paraffin sections of uveal melanomas. Doc Ophthalmol 1986;64:6976.

114. White VA, Chambers JD, Courtright PD, Chang WY, Horsman DE. Correlation of cytogenetic abnormalities with the outcome of patients with uveal melanoma. Cancer 1998;83:3549.

115. Horsman DE, White VA. Cytogenetic analysis of uveal melanoma. Consistent occurrence of monosomy 3 and trisomy 8q. Cancer 1993;71:8119.

116. Sisley K, Rennie IG, Cottam DW, Potter AM, Potter CW, Rees RC. Cytogenetic findings in six posterior uveal melanomas: Involvement of chromosomes 3, 6, and 8. Genes Chromosomes Cancer 1990;2:2059.

117. Sisley K, Rennie IG, Parsons MA, Jacques R, Hammond DW, Bell SM, et al. Abnormalities of chromosomes 3 and 8 in posterior uveal melanoma correlate with prognosis. Genes Chromosomes Cancer 1997;19:228.

118. Scholes AG, Damato BE, Nunn J, Hiscott P, Grierson I, Field JK. Monosomy 3 in uveal melanoma: Correlation with clinical and histologic predictors of survival. Invest Ophthalmol Vis Sci 2003;44:100811.

119. Damato B, Dopierala J, Klaasen A, van Dijk M, Sibbring J, Coupland SE. Multiplex ligationdependent probe amplification of uveal melanoma: Correlation with metastatic death. Invest Ophthalmol Vis Sci 2009;50:304855.

120. Kilic E, Naus NC, van Gils W, Klaver CC, van Til ME, Verbiest MM, et al. Concurrent loss of chromosome arm 1p and chromosome 3 predicts a decreased diseasefree survival in uveal melanoma patients. Invest Ophthalmol Vis Sci 2005;46:22537.

121. Husler T, Stang A, Anastassiou G, Jckel KH, Mrzyk S, Horsthemke B, et al. Loss of heterozygosity of 1p in uveal melanomas with monosomy 3. Int J Cancer 2005;116:90913.

122. Shields CL, Ganguly A, Bianciotto CG, Turaka K, Tavallali A, Shields JA. Prognosis of uveal melanoma in 500 cases using genetic testing of fineneedle aspiration biopsy specimens. Ophthalmology 2011;118:396401.

123. Werdich XQ, Jakobiec FA, Singh AD, Kim IK. A review of advanced genetic testing for clinical prognostication in uveal melanoma. Semin Ophthalmol 2013;28:36171.

124. Tschentscher F, Prescher G, Horsman DE, White VA, Rieder H, Anastassiou G, et al. Partial deletions of the long and short arm of chromosome 3 point to two tumor suppressor genes in uveal melanoma. Cancer Res 2001;61:343942.

125. White VA, McNeil BK, Thiberville L, Horsman DE. Acquired homozygosity (isodisomy) of chromosome 3 during clonal evolution of a uveal melanoma: Association with morphologic heterogeneity. Genes Chromosomes Cancer 1996;15:13843.

126. Schoenfield L, Pettay J, Tubbs RR, Singh AD. Variation of monosomy 3 status within uveal melanoma. Arch Pathol Lab Med 2009;133:121922.

127. Harbour JW, Onken MD, Roberson ED, Duan S, Cao L, Worley LA, et al. Frequent mutation of BAP1 in metastasizing uveal melanomas. Science 2010;330:14103.

128. Kilic E, van Gils W, Lodder E, Beverloo HB, van Til ME, Mooy CM, et al. Clinical and cytogenetic analyses in uveal melanoma. Invest Ophthalmol Vis Sci 2006;47:37037.

129. Damato B, Dopierala JA, Coupland SE. Genotypic profiling of 452 choroidal melanomas with multiplex ligationdependent probe



amplification. Clin Cancer Res 2010;16:608392.

130. Onken MD, Worley LA, Harbour JW. A metastasis modifier locus on human chromosome 8p in uveal melanoma identified by integrative genomic analysis. Clin Cancer Res 2008;14:373745.

131. Parrella P, Sidransky D, Merbs SL. Allelotype of posterior uveal melanoma: Implications for a bifurcated tumor progression pathway. Cancer Res 1999;59:30327.

132. Ehlers JP, Worley L, Onken MD, Harbour JW. Integrative genomic analysis of aneuploidy in uveal melanoma. Clin Cancer Res 2008;14:11522.

133. Aalto Y, Eriksson L, Seregard S, Larsson O, Knuutila S. Concomitant loss of chromosome 3 and whole arm losses and gains of chromosome 1, 6, or 8 in metastasizing primary uveal melanoma. Invest Ophthalmol Vis Sci 2001;42:3137.

134. Tschentscher F, Hsing J, Hlter T, Kruse E, Dresen IG, Jckel KH, et al. Tumor classification based on gene expression profiling shows that uveal melanomas with and without monosomy 3 represent two distinct entities. Cancer Res 2003;63:257884.

135. Onken MD, Worley LA, Ehlers JP, Harbour JW. Gene expression profiling in uveal melanoma reveals two molecular classes and predicts metastatic death. Cancer Res 2004;64:72059.

136. van Gils W, Lodder EM, Mensink HW, Kili E, Naus NC, Brggenwirth HT, et al. Gene expression profiling in uveal melanoma: Two regions on 3p related to prognosis. Invest Ophthalmol Vis Sci 2008;49:425462.

137. Petrausch U, Martus P, Tnnies H, Bechrakis NE, Lenze D, Wansel S, et al. Significance of gene expression analysis in uveal melanoma in comparison to standard risk factors for risk assessment of subsequent metastases. Eye (Lond) 2008;22:9971007.

138. Onken MD, Worley LA, Tuscan MD, Harbour JW. An accurate, clinically feasible multigene expression assay for predicting metastasis in uveal melanoma. J Mol Diagn 2010;12:4618.

139. Chappell MC, Char DH, Cole TB, Harbour JW, Mishra K, Weinberg VK, et al. Uveal melanoma: Molecular pattern, clinical features, and radiation response. Am J Ophthalmol 2012;154:227232.e2.

140. Onken MD, Worley LA, Char DH, Augsburger JJ, Correa ZM, Nudleman E, et al. Collaborative Ocular Oncology Group report number 1: Prospective validation of a multigene prognostic assay in uveal melanoma. Ophthalmology 2012;119:1596603.

Cite this article as: Kaliki S, Shields CL, Shields JA. Uveal melanoma: Estimating prognosis. Indian J Ophthalmol 2015;63:93-102.

Source of Support: Support provided by Hyderabad Eye Research Foundation, Hyderabad (SK), and Eye Tumor Research Foundation, Philadelphia, PA (CLS, JAS). The funders had no role in the preparation, review or approval of the manuscript. Conflict of Interest: None declared.


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